Assignment of the absolute configuration of the marine pentacyclic polyether (+)-enshuol by total synthesis

Article abstract of DOI:10.1002/anie.200701737

(Chemical Equation Presented) Finding its true identity: The complete stereostructure of the marine pentacyclic triterpene polyether (+)-enshuol is shown. Asymmetric total synthesis confirmed the configuration predicted on the basis of NMR spectroscopic data of the previously synthesized natural products aurilol and glabrescol, substructures of which are present in enshuol, and disproved an earlier prediction based on biogenetic considerations.

Full text of DOI:10.1002/anie.200701737

Angewandte
Chemie
DOI: 10.1002/anie.200701737
Structure Elucidation
Assignment of the Absolute Configuration of the Marine Pentacyclic
Polyether (+)-Enshuol by Total Synthesis**
Yoshiki Morimoto,* Hiromi Yata, and Yoshihiro Nishikawa
Enshuol (1), a member of a family of squalene-derived
triterpene polyethers named oxasqualenoids,[1] was isolated
from the red alga Laurencia omaezakiana Masuda sp.by
Suzuki and co-workers in 1995.[2] Although the planar
structure and partial configuration of 1 were elucidated by
spectroscopic and chemical analysis, until now the entire
configuration had not been determined.Many other types of
oxasqualenoids have been isolated;[1] however, it is often
difficult to determine their stereostructures even by modern
highly advanced spectroscopic methods, especially in the case
of acyclic systems that include stereogenic quaternary carbon
Our retrosynthetic analysis of the target molecule 9 is
shown in Scheme 2.We planned to construct the A ring by 7-
endo-trig bromoetherification of the corresponding precursor
10.The B, D, and E rings would be formed by 6- endo-tet or 5-
exo-tet epoxide opening of the corresponding bishomoepoxy
alcohols.[7] The required carbon framework (see 11) could be
assembled in a convergent manner from suitable building
blocks.
We began our synthesis with the chain extension of the
known chiral epoxide 14[4g] by using a lithio derivative of the
chiral allylic sulfide 12.[4d] The acetonide 15[8] was obtained
after desulfurization of the resulting sulfide (Scheme 3).
Deprotection of the acetonide in 15 and epoxide formation
from the vicinal diol[9] to give 17, followed by Shi asymmetric
epoxidation[10] of the alkene, furnished the diepoxy alcohol
19.The treatment of 19 with (ꢁ )-10-camphorsulfonic acid
(CSA) in dichloromethane led to a regioselective 5-exo-tet
tandem oxacyclization[7] to afford the tricyclic system of
adjacent tetrahydrofuran rings 20, which was deprotected to
give the triol 21.
At this stage, the NMR spectroscopic data obtained (in
CDCl3) for the synthetic C,D,E ring system 21 were compared
with those of natural enshuol (Scheme 4).[2] The Dd values
denote differences in the chemical shifts observed for the
synthetic and natural compounds.The chemical shifts for the
synthetic material are given in red for hydrogen atoms when
j Dd j > 0.03 ppm and for carbon atoms when j Dd j > 0.4 ppm,
except in the case of methylene carbon and hydrogen atoms.
Upon comparison of the data, we felt, from experience in our
laboratory,[4,5] that the trans,trans,trans configuration pro-
posed in 9 for the three contiguous tetrahydrofuran rings of
enshuol might be incorrect.We have previously completed
total syntheses of glabrescol[4b] and aurilol,[4g] the structures of
which are closely related to that of enshuol.When we
compared the NMR spectroscopic data that we had obtained
for glabrescol and aurilol with those of natural enshuol, we
found that the data for half of C2-symmetric glabrescol and
the left-hand side of aurilol (see structures in Scheme 4) are
almost coincident with those for the right and left halves of
natural enshuol, respectively, as shown by the presence of a
single red j Dd j value for each substructure and spectrum.
Thus, a hybrid stereostructure 22 of glabrescol and aurilol
became our next target.
ꢀ
ꢀ
ꢀ
centers, such as C10 C11, C14 C15, and C18 C19 in 1.Such
systems expose the technical limitations of the current highly
advanced NMR spectroscopic methods used for the structural
elucidation of diverse and complex natural products.[3] Such
difficulties coupled with the unique structures of the oxa-
squalenoids have prompted synthetic organic chemists to
determine the stereostructures of these natural products by
chemical synthesis.[4] Herein, we report the total assignment
of the previously incomplete stereostructure of (+)-enshuol
(see structure 22) through the first asymmetric total synthesis
of (+)-enshuol, the configuration of which is difficult to
determine by other means.
Recently, we reported the assignment of the absolute
configuration of (+)-intricatetraol (6) by chemical synthe-
sis.[4h,5] Biogenetic considerations led Suzuki et al.to suggest
structure 5 for (+)-intricatetraol (Scheme 1).[6] Therefore, in
this case, on the basis of the proposed biogenesis of 1, we
chose compound 9 as the synthetic target.Too many
stereostructures were possible for 1 if NMR spectroscopic
data alone was considered.Suzuki and co-workers also
suggested structure 9 to be the correct stereostructure of
(+)-enshuol, again on the basis of the hypothetical biogenetic
pathway.
[*] Prof. Dr. Y. Morimoto, H. Yata, Y. Nishikawa
Department of Chemistry
Graduate School of Science, Osaka City University
Sumiyoshi-ku, Osaka 558-8585 (Japan)
Fax: (+81)6-6605-2522
E-mail: morimoto@sci.osaka-cu.ac.jp
Homepage: http://www.sci.osaka-cu.ac.jp/chem/org2/org2j.html
[**] We thank Dr. M. Suzuki, University Malaysia Sabah, for kindly
providing us with copies of the 1H and 13C NMR spectra of natural
enshuol and for valuable discussions. This research was supported
by a Grant-in-Aid for Scientific Research in Basic Research (C) from
the JSPS and a Grant-in-Aid for Scientific Research in Priority Areas
(17035071) from the MEXT.
The addition of a geranyl side chain to the epoxide 14 and
subsequent Shi asymmetric epoxidation of the resulting diene
23 catalyzed by ent-18, the enantiomer of 18, provided the
diepoxy alcohol 24 (Scheme 5).The tandem oxacyclization of
24 with CSA gave the desired tricyclic ring system 25.
Cleavage of the SEM ether in 25, conversion of the resulting
vicinal diol into an epoxide, and the introduction of the diene
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 6481 –6484
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Scheme 1. Possible biogenesis proposed by Suzuki and co-workers for intricatetraol (5) and enshuol (9).
Scheme 2. Retrosynthetic analysis of the target molecule 9.
Scheme 3. Reagents and conditions: a) 12, BuLi, TMEDA, THF,
ꢀ788C, 1 h; b) Na, iPrOH, THF, reflux, 14 h, 73% (2 steps); c) aq
AcOH (80%), RT, 16 h, 100%; d) MsCl, pyridine, CH2Cl2, 08C!RT,
2 h; e) K2CO3, MeOH, RT, 40 min, 67% (2 steps); f) 18, oxone,
Bu4NHSO4, CH2(OMe)2/CH3CN/H2O, pH 10.5, 08C, 2.5 h, 97%
(d.r.>6:1); g) CSA, CH2Cl2, RT, 1 h, 53%; h) Bu4NF, THF, reflux, 18 h,
88%. Ms=methanesulfonyl, SEM=2-(trimethylsilyl)ethoxymethyl,
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
side chain with the sulfide 13[4g] yielded the bishomoallylic
alcohol 27.Shi asymmetric epoxidation of the diene 27
proceeded in a regioselective manner to provide the mono-
epoxide 28 with the terminal alkene intact.A 6- endo-tet
cyclization to form the B ring occurred regioselectively upon
treatment of the bishomoepoxy alcohol 28 with triisopropyl-
silyl triflate (TIPSOTf) and 2,6-lutidine in nitromethane at
08C for 15 min[7a] to afford the mono- and bis(triisopropylsilyl
ether)s 29 and 30, respectively, in a total yield of 71%.
After the removal of the silyl ethers in 29 and 30, cross-
metathesis of the olefin 31 with 2-methyl-2-butene in the
presence of the Grubbs second-generation catalyst 32 pro-
vided the trisubstituted alkene 33 in 97% yield.[11] Fortu-
1
nately, the H and 13C NMR spectral characteristics of the
synthetic compound 33 with the cis,cis configuration within
the D,E tetrahydrofuran rings were consistent with those
reported for the compound derived from natural enshuol by
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Angewandte
Chemie
synthetic compound 22
([a]2D8 = + 21.2
(c = 0.04,
CHCl3)) were identical to
those of the natural prod-
uct ([a]2D2 = + 22.7 (c =
1.00, CHCl3)).[2] Thus, the
entire configuration of
(+)-enshuol is shown by
the structural formula 22,
as predicted from our
NMR spectroscopic data.
In conclusion, the abso-
lute configuration of (+)-
enshuol was predicted
from NMR spectroscopic
data of previously synthe-
sized natural products and
confirmed to be that
depicted by structure 22
through the first asymmet-
ric total synthesis of the
pentacyclic polyether.In
the case of intricatetraol
(5), biogenetic considera-
tions led to the prediction
of the correct stereostruc-
ture; however, the postu-
late that the biogenesis of
Scheme 4. Comparison of the NMR spectroscopic data of our synthetic compounds with those of natural
enshuol.
opening of the A ring.[2] Finally, 7-endo-trig bromoetherifica-
tion of the trishomoallylic alcohol 33 with N-bromosuccini-
mide (NBS) in 1,1,1,3,3,3-hexafluoro-2-propanol[12] gave the
enshuol occurs via a common tetraepoxide intermediate 2 did
not.This example illustrates the important role of chemical
synthesis in combination with spectroscopic methods and
biogenetic considerations in the structure elucidation of
1
target molecule 22.[13] The H and 13C NMR spectra of the
Scheme 5. Reagents and conditions: a) geranyl phenyl sulfide, BuLi, TMEDA, THF, ꢀ788C, 1.5 h; b) Na, iPrOH, THF, reflux, 16 h, 90% (2 steps);
c) ent-18, oxone, Bu4NHSO4, CH2(OMe)2/CH3CN/H2O, pH 10.5, 08C, 2 h, 74% (d.r.>6:1); d) CSA, CH2Cl2, RT, 1 h, 66%; e) Bu4NF, THF, reflux,
22 h, 100%; f) MsCl, pyridine, CH2Cl2, 08C!RT, 1 h; g) K2CO3, MeOH, RT, 1 h, 93% (2 steps); h) 13, BuLi, TMEDA, THF, ꢀ788C, 1 h; i) Na,
iPrOH, THF, reflux, 18 h, 92% (2 steps); j) 18, oxone, Bu4NHSO4, CH2(OMe)2/CH3CN/H2O, pH 10.5, 08C, 1 h, 77% (d.r. >8:1); k) TIPSOTf, 2,6-
lutidine, CH3NO2, 08C, 15 min, 29: 22%, 30: 49%; l) Bu4NF, THF, reflux, 16 h, 92%; m) 32, 2-methyl-2-butene, reflux, 19 h, 97%; n) NBS,
(CF3)2CHOH, 4-Š molecular sieves, 08C, 10 min, 20%. Cy=cyclohexyl, Mes=mesityl.
Angew. Chem. Int. Ed. 2007, 46, 6481 –6484
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Communications
diverse and complex natural products.[3] Further structural
elucidation by chemical synthesis is in progress.
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Biomol. Chem. 2006, 4, 3220 – 3222.
[6] M.Suzuki, Y.Matsuo, S.Takeda, T.Suzuki,
Received: April 19, 2007
Published online: July 31, 2007
Phytochemistry
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[7] a) Y.Morimoto, Y.Nishikawa, C.Ueba, T.Tanaka,
Angew.
Keywords: asymmetric synthesis · configuration determination ·
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[8] All new compounds were characterized by 1H NMR, 13C NMR,
and IR spectroscopy, and by low- and high-resolution mass
spectrometry (see the Supporting Information).
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[13] The bromoetherification of 33 was attempted with NBS in
(hexyl)3P(CH2)13CH3NTf2, 2,4,4,6-tetrabromo-2,5-cyclohexadie-
none in CH3CN or (CF3)2CHOH, and Br(2,4,6-trimethylpyridi-
ne)ClO4 in CH2Cl2, CH3CN, or (CF3)2CHOH; however, the
highest yield of 22 in these experiments was 10%.
K.Ochi, M.Okada, K.Suenaga, K.Yamada,
Tetrahedron Lett.
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